Index

ABCR4, 168 Adriamycin, 86

Age-related macular degeneration (AMD), 97, 167–175

antioxidant and, 168, 171 dry stage, 167–168 incidence of, 167–168 and photoreactivity of

lipofuscin, 169–170 melanosome, 171

RPE susceptibility and adaptation to ROS, 171–172

wet stage, 168

Alkoxyl radical, 72, 96–97 Allopurinol, 185, 191 Alpha-tocopherol acetate, 160 Alzheimer’s disease, 40, 97 Amadorins, 98

Amadori rearrangements, 87–88 AMD. See Age-related macular

degeneration (AMD) Aminoguanidine, 98 AMPA-receptors, 99 Amyotrophic lateral sclerosis, 40 Anoxia, 177–179 Anthraquinones, 86 Antioxidants

AMD and, 168, 171

basal oxidant tone requirement, 19

[Antioxidants]

cooperative effects and cataract, 96–100

defence system, 13 definition, 13

diabetic retinopathy and, 159–164 dietary, 15, 20

modulation of cardiovascular disease, 11–23

oxidative events as cause of disease, 19–20

properties of melanin, 150–152 selection of, 22

strategies for future therapies, 18

supplementation and diet, 20–21 systems in mitochondria, 4

vitamins, 14–18. See also Antioxidant vitamins

Antioxidant Supplementation in Atherosclerosis Prevention study (ASAP), 18

Antioxidant vitamins atherosclerosis and, 16–18 cardiovascular disease and, 11–23

epidemiological and clinical studies, 17–18

experimental and animal studies, 16–17

210

Antioxidative strategies, for protection of cataract, 94–100

cooperative effects of antioxidative, 96–100

from oxygen stress, 94–96 Antioxidative therapies, strategies for, 22 AP-1, 12, 109

APOE, 168

Apoptosis signal-regulating kinase-1 (ASK-1), 7

ARE-Nrf2 signaling pathway, 14 Ascorbic acid, 13–15, 21, 57, 59–60, 65,

160, 183, 190 Atherogenesis, 15–16

Atherosclerosis, 11, 22–23, 40, 97, 100 and antioxidant vitamins, 16–18

and oxidative stress, 15–16

Autocrine signaling, and IFNg stimulation in EAU, 126–127

Beaver Dam Eye Study, 168 Benzoquinones, 86 Bestrophin, 168

Bilirubin, 13–14

Blue Mountain Eye Study, 168 Bone marrow-derived macrophages

(BM-Mj), generation of, 122 Bordetella pertussis toxin (PTX), 122 Bovine RPE-choroid complexes

antibody staining of tyrosinase in, 201 organ culture of, 198–199, 202

Bowman’s layer, 56

Brain, resistance to ischemia, 179–181 Bullous keratopathy, 61–63 Buthionine sulfoximine (BSO), 47–48

Caffeine, 99

Calcium-dependent protein kinase C (PKC), 187

Calcium dobesilate, 191

Cancer and oxidative stress, 11, 40 Cardiovascular disease

antioxidants

atherosclerosis and vitamins, 16–18 modulation of, 11–23

vitamins, 11–23

Index

[Cardiovascular disease] epidemiological and clinical studies,

17–18

oxidative stress and, 15–16 ROS and, 12–13

Carnitin, 15 b-carotene, 99, 160

Carotenoids, 13–14, 21, 81–82, 98, 168–169

Carrageenan-gamma radiation, 100 Caspase-3, 187

Catalase, 13, 35, 71–72, 179, 190–191

Cataract

diabetic events, 87–89

effects of antioxidants, 96–100 herbal extracts, 97–100 LDL oxidation, 96–98

effects of light, 83–86 experimental induction, 89

first biochemical signs of, 89–90 formation by light, 85

forms of, 83–84

intrinsic light reactions, 90 models for investigating topical

penetration rates, 91–94 modes of induction, 83–84 naphthalin induced, 89

prevention in model reactions in vitro and ex vivo, 90–92

protection by antioxidative strategies, 94–100

cooperative effects of antioxidative, 96–100

from oxygen stress, 94–96 protection from oxygen stress,

94–96

by detoxifying enzymes, 94–95 by phenolic derivatives, 95–96

protein glycosylation, 87–89 reductive events and, 86–87

Cataractogenesis, mechanisms of, 89 Ccl2, 168

CD18, 15

CD11b, 15

CD4+ T cell, 122, 142

CD4+ Th1 mediated disease, 121. Cell redox environment, 4

Index

Cell signaling

basal ROS tone for, 19 and gene expression, 8

Cellular glutathione analysis with CDNB, 50

DTNB, 48–50 mBBr, 48–50

concentrations modulation and determination, 45–52 determination methods, 48–50

diazenedicarboxylic acid reaction with, 47 experimental modulation, 46–48 menadione and concentration of, 50–52 reaction of diamide with, 47

reaction of diethyl maleate with, 47–48 Central retinal artery occlusion, 179 Ceruloplasmin, 13

Chemotaxis, 15 Chesapeake Bay Study, 168 Chlorodiazepoxides, 85

1-chloro-2,4-dinitrobenzoic acid (CDNB), 50

Chlorothiazines, 85

Choroidal neovascularization (CNV), 168 Collagen, 15

Cornea. See also Corneal diseases antioxidants, 58–60

ascorbic acid, 59–60

superoxide dismutases (SOD), 58–59 endothelium of, 57–58

stroma of, 57 Corneal diseases

bullous keratopathy, 61–63 endothelial cell loss after

phacoemulsification cataract surgery, 58, 64–65

endothelial cell loss in inflammatory eye diseases, 63–64

epithelium cell loss, 56–57

after phacoemulsification cataract surgery, 64–65

in inflammatory eye diseases, 63–64

Fuchs endothelial dystrophy, 61–63 keratoconus, 60–61

oxidants in, 55–65 ROS and, 55, 63–65

211

CR-6 (3,4-dihydro-6-hydroxy-7-methoxy- 2,2-dimethyl-1(2H)-benzopyran), 161–164

Cyclic photosystem I, 81 Cyclooxygenases-1 (Cox 1), 35 Cyclooxygenases-2 (Cox 2), 35 Cytochrome c, 169

displacement in EAU, 138–139, 142 location and function in mitochondria,

141–142 Cytokine analysis, 123

Cytosolic copper-zinc-containing SOD (SOD1), 58

Descemet’s membrane, 57 Desferrioxamine, 191

Detoxification, by enzymatic processes, 94–95

Diabetes mellitus, 159 Diabetic retinopathy, 179

and antioxidants, 159–164 electroretinogram and, 162–164 peroxynitrite scavengers, 160–162

Diclofenac, 99

Dietary antioxidants, 15, 20 Diethyl maleate (DEM)

cellular glutathione reaction with, 47–48 glutathione levels in cells exposed to, 52

Dihydro-thioctic acid, 91 Dihydroxyfumaric acid (DHF),

autoxidation of, 88 Dihydroxyphenylalanin (DOPA), 89 5,50-Dithiobis-2-nitrobenzoic acid

(DTNB), 48–49

Ebselen, 160, 164

Electroretinogram (ERG), and diabetic retinopathy, 162–164

Electroretinography and ischemia, 181 Ellman’s reagent, 48

ELOVLA4, 168

Endothelialleukocyte adhesion molecule (ELAM-1), 75

Endothelial nitric oxide synthase (eNOS), 12, 21–22, 108, 112, 186–187

Endotoxin induced uveitis (EIU), 111

212

Estrogens, 85 Eumelanin, 148, 153–154

Experimental autoimmune uveoretinitis (EAU)

autocrine signaling and IFN g stimulation in, 126–127

cytochrome c displacement from electron transport assembly in, 138–139, 142

IFNg stimulation in, 126–127 infiltrating macrophage function

during, 123–125

localization of nitrated retinal protein in, 137–139

nitration and release of cytochrome c in, 139

nitric oxide in, 107–114 pathogenesis, 111–113 pathology, 108–111

therapeutic strategies to reduce tissue damage, 113–114

TNF activation and, 121–128 peroxynitrite role in, 139–142 retinal microenvironment during,

123–125

retinal morphology and protein nitration during, 135–136

superoxide and nitric oxide in, 132–139 TNFa neutralising activity, 125

Extracellular SOD (SOD3), 58 corneal endothelium of, 63 immunohistochemical staining for,

58–59 in KC, 61

Fasþ T cells, 113 Fenton reaction, 34 Ferritin, 13 Fibulin-3, 168 Flavonoids, 14, 21

Flavoprotein (FP)-oxidoreductases, 86 FLICE-inhibitory protein (FLIP),

108, 114 Flupirtine, 191 FPLC

chromatography, 90–91

Index

Free radicals, 34 biology, 1–8

melanin interaction with, 150–152 Fuchs endothelial dystrophy, 61–63 Furocumarines, 85

Ganglion apoptosis, oxidative stress in, 76–78

Ganglion cell apoptosis, 74, 76–78

axons and glaucoma, 74–75 death in glaucoma, 72–74

Gene expression, and cell signaling, 8 Ginkgo biloba extracts (GBE), 97–100,

183, 185 Ginkgolide A, 100 Ginkgolide B, 99–100 Ginkgolide J, 99 Glaucoma, 179, 188

ganglion cell death in, 72–74 initiation for loss of vision in patients

of, 72–73 mitochondria and, 74–75 oxidative stress

in ganglion apoptosis, 76–78 involvement in, 71–78

and raised IOP, 75–76 pathogenesis, 71–78

plasma analysis in POAG for, 75 retinal ganglion cell axons and, 74–75 risk factors in, 72–73

Glutamate-induced cytotoxicity, 99 Glutamate-induced neurotoxicity, 100 g-Glutamylcysteine synthetase (GCS),

47–48 g-Glutamylcysteinylglycine (GSH). See

Glutathione

Glutathione disulfide (GSSG), 4, 39, 46–52

Glutathione (GSH), 4, 13–14, 71–72, 75–76, 98, 100, 164, 184. See also Cellular glutathione

oxidative stress and, 76 structure, 45–46

Glutathione peroxidase, 13, 35, 179, 190 Glutathione reductase, 13

Index

Glutathione S-transferase isoenzymes, 75 Glutathione S-transferases (GSTs), 47, 50,

95

Gluthathione redox cycles, 35 Glycaemia, 161

GPx activity, 161–162 Green tea, 160 Griseofulvin, 85

GSH peroxidase. See Glutathione peroxidase

Hard exudates, 168

Health and disease, nitric oxide related oxidants in, 33–41

Herbal extracts, effect on cataract, 97–100

HIF-1, 12 HTRAI, 168

Human RPE melanin, 154–155. See also Retinal pigment epithelium (RPE)

Hydrogen peroxide, 12, 33–35, 71–72, 75, 111, 171–172, 179, 183, 205

in cell signaling and gene expression, 8 Hydroperoxide, 72

6-hydroxykynurenic acid (6-HKA), 99 Hydroxyl radical, 12, 33–34, 71–72, 179,

183, 205 Hyperglycaemia, 161

Hypericum perforatum extracts, 97 Hypochlorite, 12

Hypochlorous acid, 12, 34–35 Hypoglycaemia, 181 Hypoxia, 177–178

IL-1, 109

IL-1b, 15, 110–111

IL-2, 110–112, 122–123, 127

IL-4, 15, 107, 109, 112–113

IL-6, 110–111

IL-8, 111

IL-10, 107, 112, 114, 123

IL-12, 123

IL-17, 113

IL-23, 113

213

Inducible NO synthase (iNOS or NOS2), 108–114, 185, 187

immunohistochemical analysis

of macrophages during EAU, 123–124

INF-a, 109

INF-g, 107, 109–114, 121–128 stimulation in EAU and autocrine

signaling, 126–127 Inflammatory eye diseases, corneal

endothelial cells loss in, 63–64 Interferon-gamma. See INF-g Interleukins 4. See IL-4

Interleukins 1b. See IL-1b Interphotoreceptor retinoid-binding

protein (IRBP) peptide 1–20, 122

Intraocular pressure (IOP), 71–72, 75–76 Intravascular ultrasonography study

(IVUS), 18

Intrinsic light reactions, and cataract, 90 IRBP. See Interphotoreceptor retinoid-

binding protein (IRBP) peptide Iron II+ oxidation process, 82 Ischemia, 177–178

retina and brain resistance to, 179–181. See also Retinal ischemia

Ischemic cascade, 188

Janus protein tyrosine kinases, 12 Juglone, 86

Kelch-like ECH-associated protein 1 (Keap 1), 14

Keratoconus (KC), 60–61 a-Keto-S-methyl-butyric acid (KMB), 90 Kynurenic acid, 99

L-arginine, 112, 140, 184, 186 L-citrulline, 184 L-3,4-dihydroxyphenylalanine (L-DOPA),

198–200

LDL oxidation, effects on cataract, 96–98

214

LDL protection, cooperative effects of rutin and ascorbate in, 97–98

Lipid peroxidation, 99 radicals, 34–35

Lipofuscin, 169–172 photoreactivity of, 169–170

Lipoic acid, 13–14, 160, 183, 191 L-NAME, 112, 187

L-tyrosine, 198, 201 Lutein, 160, 164, 169, 171

Macrophage cultures, cytokine stimulation of, 122–123

Macular degeneration, ROS role, 167–172 Manganese superoxide dismutase, 40 Mannitol, 184, 191

Melanin, 169

biosynthesis, 147–152, 197–198 and oxidative reactions, 147–155 properties

antioxidant properties, 150–152 for photoprotection, 147–152 pro-oxidant and phototoxic action,

153–155

rate constants of interaction with free radicals and singlet oxygen, 150–151

Melanogenesis, 148

Melanosomes, 148 photoreactivity of, 171 in RPE cells, 205

Menadione (2-methyl-1,4-naphthoquinone) glutathione levels in cells exposed to, 52 Michael addition of thiols/thiolates to, 51 redox cycling of, 50–52

Metalloproteins, 40 Metallothioneins, 71–72

Michael addition of thiols/thiolates, to menadione, 51

Mitochondria, 22, 140–142 antioxidant systems, 4

cellular sources of superoxide anion, 2, 12 features and cell function, 5–6 generation of signaling molecules, 6–8 and glaucoma, 74–75

location and function of cytochrome c in, 141–142

Index

Mitochondrial Manganese-containing SOD (SOD2), 58

Mitochondrial respiratory chain, 6–7 Mitochondrial SOD, 35 Mitogen-activated protein kinases, 12 Mitosis, 58, 62

Monobromobimane (mBBr), 48–49 Muller cells, 112, 163, 183, 186 Myocardial contractile failure, 40 Myricetin, 99

N-acetyl cysteine, 160 NADPH oxidase, 2, 12, 36, 94

NAD(P)H oxidoreductases (diaphorases), redox substrates of, 87

NADPH-quinone reductase, 95 Naphthoquinones, 86

Neural cell apoptosis, 160–161 Neurodegenerative disorders, 11 Neuronal hypoxia, 98

Neuronal NO synthase (nNOS or NOS1), 108, 186

NFkB, 12, 109, 185 Nitrated retinal proteins

identification of, 133–137 localization in EAU, 137–139

Nitrate-respiration, 82

Nitric oxide, 12, 34–35, 71–72 biological effects, 109

in cell signaling and gene expression, 8 in EAU, 107–114, 132–139

pathogenesis, 111–113 pathology, 108–111

TNF activation and, 121–128 effects on immune function, 108–109 generation of RNS and, 33

induced tissue damage, 113–114 induce protein S-glutathionylation, 39 induction in EAU, 111–113 quantification of synthesis of, 123 related oxidants in health and disease,

33–41

therapeutic strategies to reduce tissue damage by, 113–114

univalent oxidation of, 2–3

Nitric oxide synthases (NOS), 37, 108–114, 132, 140, 142, 163, 184, 186

Nitrofuran, 86

Nitrogen, oxidation of, 2–3 Nitrosyl radical, 182 NMDA-receptors, 99 NOS2 KO mice model, 111 NOS uncoupling, 37

Nrf-2-Keap1-ARE activators, 20 NSAIDs (non-steroidal anti-inflammatory

drugs), 94

Ocular diseases, and ROS, 94 Ophthalmic artery occlusion, 179 Oxidants, in corneal diseases, 55–65 Oxidative reactions, and melanin,

147–155 Oxidative stress

and atherosclerosis, 15–16 concept of, 1–2, 71

in ganglion apoptosis, 76–78 glutathione and, 76

involvement in glaucoma pathogenesis, 71–78

as neuroprotective strategy in retinal ischemia, 190–191

in pathogenesis of retinal ischemia, 177–192

and raised IOP, 75–76

reduction in retinal disease, 197–206 ROS and RNS and, 33

Oxygen toxicity, 82

univalent reduction of, 2–3 Oxygen stress

cataract protection from, 94–96 by detoxifying enzymes, 94–95 by phenolic derivatives, 95–96

Paraquat, 86, 171 Parkinson’s disease, 40, 97

Pathogen-associated molecular pattern (PAMP), 127

Pecking order principle, 96–97 Penetration rates, determination of, 91–94 Penicillin, 198

Peroxiredoxins, 13 Peroxyl radical, 71–72

Peroxynitrite, 12, 34–35, 72, 111–112, 179, 182

and ocular inflammation, 131–142 role in EAU, 139–142

scavengers and diabetic retinopathy, 160–162

Phacoemulsification cataract surgery, corneal endothelial cell loss after, 64–65

Phagocytosis assay for, 199

induced tyrosinase expression, 204 of ROS, 112, 198, 201, 203–204

Phenolic redox reactions, 96 Phenothiazines, 85 Pheomelanin, 148, 153 Phosphoglycerate mutase, 140 Phosphoinositide-3-kinase, 12 Phospholipase C-g1, 12 Photo-ageing, 149 Photodynamic drugs, 84–85

Photoprotection, melanin properties for, 147–152

Photoreactivity

of lipofuscin, 169–170 of melanosomes, 171 of retina, 168–169

Photoreceptor cells, 140 Photosystem I and II, 81–82 Photothrombosis retinal ischemia

model, 181

Phototoxic action, of melanin, 153–155 Polyphenols, 13–14, 81

Porphyrin, 169

Postranslational modifications in proteins by ROS and RNS, 38. See also Protein

post-translational modifications Primary open-angle glaucoma (POAG),

71, 75 Progesterones, 85

Pro-oxidant, properties of melanin, 153–155

Propolis, 99 Protein

glycosylation, and cataract, 87–89 Protein post-translational modifications by reactive oxygen and nitrogen

species, 3–4

216

[Protein post-translational modifications] by ROS and RNS, 37–41

S-Glutathionylation, 37–39 S-nitros(yl)ation, 38–40 tyrosine nitration, 38,

40–41 Pycnogenol, 99, 160 Pyridorin, 98 Pyridoxamine, 98

Pyrroloquinolin quinones (PQQ), 86

Quercetin, 99

Radiation-induced cataract, 100 Reactive nitrogen species (RNS).

See also ROS and RNS generation of, 3, 33

postranslational protein modifications, 33–34

protein post-translational modifications by, 3–4

Reactive oxygen species (ROS). See also ROS and RNS

AMD and, 167–172 cell damage by, 179

and corneal diseases, 55, 63–65 intracellular concentrations of, 71 mediated cell damage, 12

ocular diseases and, 94 phagocytosis of, 112, 198, 201,

203–204

and photoreactivity of lipofuscin, 169–170 melanosome, 171 retina, 168–169

protein post-translational modifications by, 3–4

RPE susceptibility and adaptation to, 171–172

signaling pathways, 12 sources, 12–13, 77 specific removal of, 5

Redox cell signaling, 3 Reductive events, and cataract,

86–87 Respiratory burst, 83

Index

Retina

photoreactivity of, 168–169 resistance to ischemia, 179–181.

See also Retinal ischemia tyrosine-nitrated proteins in, 138, 142

Retinal ganglion cell axons, 71, 74–75 and glaucoma, 74–75

Retinal ischemia

counteracting oxidative stress as neuroprotective strategy, 190–191

events associated with, 188–189 free radical role, 182–185 model of, 179–180

neurological mechanisms, 181–182 nitric oxide free radical in, 186–187 ocular diseases implicated in, 178 oxidative stress role in pathogenesis

of, 177–192

therapeutic intervention strategies for, 190

Retinal myeloid cell isolation, 122 Retinal pigment epithelium (RPE),

110–112, 153–155, 185, 197–204 susceptibility and adaptation to ROS,

171–172

Retinal proteins in uveitis, nitration of, 132–135

Riboflavine, 83

ROS and RNS characteristics of, 33–35 formation of, 35–37 oxidative stress and, 33

postranslational modifications, 38 protein modification produced, 37–41

S-Glutathionylation, 37–39 S-nitros(yl)ation, 38–40 tyrosine nitration, 38, 40–41

sources, 12–13, 36 Rotterdam study, 168 RPE65, 168

Scavenger receptors (SRA), 15 Selenite-induced cataract, 99 Selenium, 160

Sensory retinal detachment, 168 S-Glutathiolation. See S-glutathionylation

Index

S-Glutathionylation, 3–4, 34, 37–39 Signaling molecules, mitochondrial

generation of, 6–8 Singlet oxygen, 71–72, 83, 86

melanin interaction with, 150–152 S-nitrosation. See S-nitros(yl)ation S-nitros(yl)ation, 3, 34, 38–40 Sodium arsenite, 171

Staurosporine (ST)-induced neuronal apoptosis, 99

STNFr-Ig therapy, 125–126 Streptomycin, 198 Subarachnoid hemorrhage, 99 Sulfonamides, 85

Sulfonic urea, 85

Superoxide anion, 12, 34, 71–72, 75, 205 in cell signaling and gene expression, 8 in EAU, 132–139

sources of, 2, 33

Superoxide dismutases (SODs), 13, 34–35, 57–59, 71–72, 76, 95, 99, 140, 160, 168, 172, 179, 183, 190–191

Taurine, 160

T cell apoptosis, 113–114 Tertbutylhydroperoxide, 171 Tetracyclines, 85

TGF-b, 107, 109, 111–112, 122–125 Th1 cytokines, 107, 110, 112, 124 Th2 cytokines, 108–109, 112 Thiol-disulfide oxidoreductases, 13 Thioredoxin, 183

T lymphocytes, 110

TNF-a, 76, 109–110, 113–114, 121, 122–128, 142

TNFRp55-/- mice, 122, 126–127

role in autocrine signaling following IFN g stimulation in EAU, 126–127

a-Tocopherol, 13–15, 17–19, 21, 96, 161, 171, 190

b-Tocopherol, 15 d-Tocopherol, 15 g-Tocopherol, 15

Toxic lipoprotein degradation, 95 Transferrin, 13

Transition metal catalyzed oxidations, 88

217

Triacetylphenolisatin, 85 Trimetazidine, 191 Trolox, 57, 160

Tumour Necrosis Factor-alpha (TNF-a). See TNF-a

Tyrosinase

antibody staining in bovine RPE cells, 201 DOPA oxidase activity of, 200–201 electron-microscopical localization of,

199–201 functions, 205–206

immunocytochemistry, 203 immunodetection of, 199–200 phagocytosis-induced expression,

204–205

rod outer segments isolation, 199 ROS impact on activity of, 204 tyrosine hydroxylase activity of,

200–201, 203 Tyrosine nitration, 38, 40–41

Ubiquinol, 13–14 Ubisemiquinone, autoxidation of, 2 Univalent reduction of oxygen,

mechanisms, 2–3 Uric acid, 13–14, 190

Uveitis, nitration of retinal proteins in, 132–135

VCAM-1, 15 Vitamin A, 71–72

Vitamin C, 13–15, 17, 21, 57, 59, 81, 98–99, 160, 168

Vitamin D, 71–72

Vitamin E, 13–15, 17, 19, 21, 57, 71–72, 81, 98, 168, 183, 191

Voltage dependent anion channels (VDAC), 7

Xanthine oxidase, 12, 36, 56, 185 Xanthurenic acid, 85–86

Zeaxanthin, 169, 171

Zeta-crystallin, 95

Zinc, 160